Most inbred mice (29 out of 31 tested) are immunologically unresponsive to a single injection of adjuvant-free beta-D-galactosidase (Z). Two genetic loci, one dominant, Ir-Z1, the other recessive, ir-Z2, controlling this unresponsiveness have recently been found. These genes segregate as autosomal single loci and are not closely linked to either the H-2 or the Ig-1 region. It is proposed to study the function of Ir-Z genes at the genetic and cellular level. For this, congenic and coisogenic strains carrying either Ir-Z1 or ir-Z2 will be constructed against a C57BL/6j genetic background. Subsequently, cell-to-cell interactions will be studied by adoptive transfer experiments and by in vitro cultures. The methdology available for studying immune responsiveness to Z is such that activating antibody can be detected at the single molecule level and antigen-binding cells can be easily enumerated. The objective is to establish the type of cell in which the products of the Ir-Z genes are expressed and ultimately, to isolate and characterize the gene products.